1,2,5-TRIAZEPANE DERIVATIVES HAVING beta;-AMINO ACYL GROUP, ITS PHARMACEUTICAL ACCEPTABLE SALTS AND PREPARATION PROCESS THEREOF

摘要

A 1,2,5-triazepane derivative showing excellent DPP-IV inhibitory activity is provided to be effectively used for preventing or treating diseases mediated by DPP-IV such as insulin-dependent, insulin non-dependent diabetes, arthritis, obesity, osteoporosis, and damaged glucose resistance. A 1,2,5-triazepane derivative having a beta-amino group is represented by the formula(1), wherein R1 is a group represented by the structural formula(1-1) or (1-2); R2 is H, C1-6 alkyl, or a group represented by the structural formula(1-3); R3 is H, C1-6 alkyl, C3-6 cycloalkyl, CH2CO2R^b, COCO2R^b, pyrazine, and a group represented by the structural formula(1-4), (1-5) or (1-6); R^a is independently H, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, OCF3, halogen, CN, CF3, COOR^b or NR^bR^c; each R^b and R^c is independently H, C1-6 alkyl or C3-6 cycloalkyl; R^d is C1-6 alkyl, trifluoromethyl, and a group represented by the structural formula(1-1), (1-7), (1-8), or (1-9); R^e is C1-6 alkyl, C3-6 cycloalkyl, and a group represented by the structural formula(1) or (2); R^f is H, halogen, NR^bR^c, tetrazole, proline, and a group represented by the structural formula(1-10), (1-11), (1-12), or (1-13); A is CH, N, O or S; B is H, C1-6 alkyl, C3-6 cycloalkyl, benzyl or CO2R^d; X is O or S; and n is 0 or 1. A method for preparing the 1,2,5-triazepane derivative comprises the steps of: (a) subjecting an amino acid represented by the formula(2) and 1,2,5-triazepane to a condensation reaction to prepare a compound represented by the formula(4); (b) reacting the compound of the formula(4) with an electrophilic compound substituted with R2 to prepare a compound represented by the formula(5); and (c) deprotecting the compound of the formula(5). A pharmaceutical composition for preventing or treating diseases mediated by DPP-IV comprises an effective amount of the 1,2,5-triazepane derivative or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.